Project Summary/Abstract This proposal focuses on the oncogenic CRTC1-MAML2 fusion that underlies the development of mucoepidermoid carcinomas (MEC), the most common type of salivary gland cancers. Patients with advanced, metastatic and recurrent MECs have poor outcomes and no targeted therapy is currently available. A comprehensive understanding of functions and mechanisms of this oncogenic fusion is essential for uncovering effective diagnostic and therapeutic approaches. We demonstrated that the CRTC1-MAML2 fusion is a major driver for MEC initiation and maintenance. Our investigations into the CRTC1-MAML2-induced oncogenic transcriptional program implicated long noncoding RNAs (lncRNAs) in MEC tumorigenesis and maintenance. LncRNAs belong to a novel class of gene regulators with emerging roles in human cancer and have the potential to serve as diagnostic markers due to their tissue and disease specificity. However, the involvement and mechanistic basis of lncRNAs remain poorly defined in MEC. Moreover, our data revealed the interaction of the CRTC1-MAML2 fusion with the transcription factor CREB is critical for inducing the major oncogenic transcriptional program; thus, targeting this interaction interface will have the advantage of blocking multiple critical fusion target genes/pathways. However, the significance of this fusion interaction as a therapeutic target remains to be tested in vivo. Therefore, the objectives of this proposal are to elucidate the lncRNA aspect of the oncogenic transcriptional program in CRTC1-MAML2- driven MEC and the significance of the critical fusion protein interaction governing the oncogenic transcriptional program in MEC. Two aims are proposed to test the overall hypothesis that the CRTC1-MAM2 fusion induces a unique lncRNA program in promoting MEC and that the CRTC1-MAML2/CREB interaction is critical for inducing the major oncogenic transcriptional program in MEC. Consequently, critical lncRNAs and fusion interaction can be targeted for MEC inhibition. Aim 1 will investigate the mechanisms and targeting of lncRNAs in CRTC1- MAML2 fusion-driven tumorigenesis. Aim 2 will Investigate the significance and targeting of the CRTC1-MAML2 fusion/CREB interaction in MEC. The completion of these proposed studies will uncover new mechanistic and functional insights into lncRNAs and the CRTC1-MAML2 oncogenic fusion and reveal new approaches for blocking MEC. We anticipate that these efforts will enhance our understanding of the CRTC1-MAML2 fusion oncogene and MEC biology and lead to the identification of novel diagnostic and therapeutic strategies.